Review ArticleThe Role and Regulation of Pulmonary Artery Smooth MuscleCells in Pulmonary Hypertension

Shixin He, Tengteng Zhu, and Zhenfei Fang

Department of Cardiology,�e Second Xiangya Hospital of Central South University, No. 139, Middle Ren-Min Road, Changsha,Hunan 410011, China

Correspondence should be addressed to Zhenfei Fang; fangzhenfei@csu.edu.cn

Received 5 December 2019; Accepted 20 July 2020; Published 12 August 2020

Academic Editor: Salvatore Corrao

Copyright © 2020 Shixin He et al. +is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Pulmonary hypertension (PH) is one of the most devastating cardiovascular diseases worldwide and it draws much attention fromnumerous scientists. As an indispensable part of pulmonary artery, smooth muscle cells are worthy of being carefully investigated.To elucidate the pathogenesis of PH, several theories focusing on pulmonary artery smooth muscle cells (PASMC), such ashyperproliferation, resistance to apoptosis, and cancer theory, have been proposed and widely studied. Here, we tried tosummarize the studies, concentrating on the role of PASMC in the development of PH, feasible molecular basis to intervene, andpotential treatment to PH.

1. Introduction

Pulmonary hypertension (PH) is a serious global healthproblem, which is characterized by progressing elevatedpulmonary pressures and right heart failure, and mainlyaffects childbearing women [1].+emean time from onset ofsymptoms to diagnosis is about 2 years, the mean survivaltime of idiopathic/heritable pulmonary arterial hypertensionpatients from treatment initiation is about 14.7 years, andthe 10-year survival rates are 69.5% [2, 3]. Based on recentestimates, in the global population, the prevalence of PH isabout 1%, while for individuals aged over 65 years, thenumber increases to 10%. What is more, about 80% of PHpatients are living in developing countries [4].

+e feature of PH is intense remodeling of small pul-monary arteries by myofibroblast and smooth muscle cellproliferation, and for familial pulmonary arterial hyper-tension, the bone morphogenetic protein type II receptor(BMPR-II) mutation in pulmonary artery smooth musclecells contributes to abnormal growth responses to thetransforming growth factor (TGF)-beta/bone morphoge-netic protein (BMP) [5]. Compared to previous belief thatvasoconstriction acts a vital role in PH pathogenesis [6, 7],there is a tendency to think that excessive proliferation and

resistance to apoptosis of PASMC and pulmonary arteryendothelial cells (PAEC) are the crucial components ofpulmonary vascular remodeling [8]. PASMC has beenwidely proved to play an important role in the developmentof various types of pulmonary hypertension. Differentmechanisms finally lead to uncontrolled proliferation ofPASMC through apoptosis resistance, activated hypoxia-induced factor (HIF), HDAC modification, and inflam-mation, resulting in pulmonary hypertension [9, 10].

According to similar pathophysiological mechanisms,clinical presentation, haemodynamic characteristics, andtherapeutic management, the clinical classification of PH isintended to categorize multiple clinical conditions into fivegroups [11]. Here, we mainly talk about WHO group 1pulmonary arterial hypertension (PAH). To offer moresuitable treatment and precisely evaluate patients’ clinicaloutcome, the following parameters appear to have thegreatest predictive capability: functional class, six-minutewalk distance (6MWD), N-terminal pro-brain natriureticpeptide/brain natriuretic peptide (NT-proBNP/BNP) levels,cardiac index, right atrial pressure, and mixed venous ox-ygen saturation (SvO2) [12, 13]. Specific drug treatment ofWHO group 1 PAH by targeting the nitric oxide, endothelin,and prostaglandin pathways has been the standard since

HindawiInternational Journal of HypertensionVolume 2020, Article ID 1478291, 10 pageshttps://doi.org/10.1155/2020/1478291

2003. Recently, based on different risk stratification, mon-otherapy or dual-combination therapies, including maci-tentan and sildenafil, riociguat and bosentan, selexipag andendothelin receptor antagonist (ERA) or phosphodiesteraseinhibitor (PDE5i), or both, are recommended [14, 15].

2. Histopathology of Lungs in PH

2.1. Histology of Normal Lung Vessels. +e major role of theright ventricle (RV) is to pump all the blood it receives perbeat into the pulmonary circulation without elevating rightatrial pressure. Normally, blood flow varies with minimumchanges in pulmonary arterial pressure. Although the totalcompliance of the pulmonary circulation is about one-seventh that of the systemic circulation, it stores much lessblood and has the ability to collapse pulmonary vessels aswell as have them distended. +us, the pulmonary circu-lation is able to accommodate increased blood volumeswithout increasing pulmonary artery pressure as much aswould occur on the systemic circulation [16, 17].

2.2. Histopathology of PAHLungVessels. In 1958, Heath andEdwards [18] first described the histologic features of hy-pertensive pulmonary vascular structure changes into sixgrades in patients with congenital septal defects of the heart.+e six grades included retention of fetal type pulmonaryvessels, medial hypertrophy with cellular intimal reaction,progressive fibrous vascular occlusion, progressive gener-alized arterial dilatation with the formation of complexdilatation lesions (plexiform lesions), chronic dilatation withformation of numerous dilatation lesions and pulmonaryhemosiderosis, and necrotizing arteritis. It is widely acceptedthat higher grade is related to worse pulmonary vessels andright heart function. Compared to the control groups, intimaand intima plus media fractional thicknesses of pulmonaryarteries were increased in the PAH group, in accordancewith pulmonary haemodynamic measurements. +ere wereremarkable perivascular inflammation in a mass of PAHlungs and correlated with intima plus media remodeling[19].

Pulmonary vasoconstriction caused by hypoxia wasstudied widely in PH [7]. As a result of global pulmonaryhypoxic vasoconstriction, the right ventricular afterloadcould increase. Chronic hypoxia-induced PH is partly due toinitial pulmonary artery contraction. Pulmonary arterypressures are higher in high-altitude dwellers with chronicmountain sickness, a syndrome including dyspnoea, fatigue,poor sleep, headache, and cyanosis. Hypoxic pulmonaryvascular remodeling also contributes to PH and begins todevelop within the first hours of hypoxic exposure. Hypoxia-induced PH in humans or animals is generally mild ormoderate, but with a substantial afterload on the rightventricle during exercise. In vitro, hypoxia was reported toinhibit myocardial fibre contractility. Pulmonary vascularcontraction plays an important role not only in hypoxic PH,but also in pulmonary arterial hypertension (PAH). Currentpharmacological therapies for PAH mostly target pathwaysregulating endothelial factors with vasoconstrictive/

vasodilatory and have made great achievements in im-proving the exercise capacity, haemodynamics, and time toclinical worsening of PAH patients.

It is increasingly believed that although vasospasm acts arole, pulmonary hypertension is an obstructive lung pan-vasculopathy and different forms of PH present with either apredominance of pulmonary arterial remodeling or veinremodeling or a variable contribution of both [20]. Obvi-ously, there is medial and adventitial thickening of thepulmonary muscular and elastic vessels. +e medial thick-ening is believed to result in hypertrophy and increasedaccumulation of smooth muscle cells as well as increaseddeposition of extracellular matrix proteins, predominantlycollagen and elastin. +e extent of structural changes, in-cluding SMC proliferation, hypertrophy, matrix proteinproduction, and recruitment of adventitial or circulatingcells, in the medial compartment of the pulmonary arterialwall partly determined the severity of chronic hypoxicpulmonary hypertension [21].

3. The Alteration of PASMC in PH

Data from post-mortem studies demonstrated medial hy-pertrophy, PASMC hyperproliferation, and muscle exten-sion into distal arterioles, with important variability betweenindividuals [22–25]. +e accurate regulation of the balancebetween PASMC proliferation and apoptosis is significant inmaintaining the normal integrity of structure and functionin the pulmonary vessels. However, in severe angioproli-ferative PAH, this balance seems to be broken, followingincreased PASMC proliferation and decreased apoptosis,resulting in vessel wall thickening and vascular remodeling[26–31]. Contrast to previous belief that the relationshipbetween pulmonary artery endothelial cells (PAEC) andPASMC is a simple one-way interaction from the endo-thelium to the PASMC, now it is more likely to believe thatmore complicated interactions exist between them [32–34].Under abnormal or irritant conditions, the intricate inter-action of PAEC and PASMC can be altered in the long termso that vascular proliferation and vasocontractility are en-hanced further, which leads to PAH and right heart failure[35–38]. Owing to the characteristics of hyperproliferationand resistance to apoptosis of PASMC in PAH, there is anargument that PAH has something to do with cancer. At themolecular level, PASMC of PAH exhibits many featuressimilar to cancer cells, which gives the chance to explorepotential therapeutic treatments used in cancer to cure PAH[8, 39, 40].

4. Possible Pathways to Act on PASMC

4.1. Role of Ion Channels. It is well known that ions playmany important roles in cell potential, cell contraction, andpH homeostasis, which can influence the proliferation andapoptosis of PASMC. Some studies demonstrated that de-crease of K+ channels affected the PASMC depolarization,then facilitated vascular remodeling, and inhibited PASMCapoptosis. In PAH rat models, restoration of K+ channelsactivity and expression, using dehydroepiandrosterone or

2 International Journal of Hypertension

dichloroacetate, reduced pulmonary vascular remodeling.However, the exact mechanisms by which K+ channels acton PASMC are still controversial [41–51]. Lv et al. foundincreased expression of MicroRNA-206 suppressed potas-sium voltage-gated channel subfamily A member 5 (Kv1.5)and promoted the PASMC proliferation [52].

+e elevated concentration of intracellular Ca2+ wasfound in PAH animal models and patients. +is kind ofphenomenon was not realized through activation of voltage-gated calcium channels (VGCC), but by increase of ca-nonical transient receptor potential (TRPC) proteins, whichinvolved Ca2+-permeable nonselective cation channels(NSCCs). Increased abundance of NSCCs was detected inPAH rat models and patients and inhibition of NSCCs,either pharmacologically or by RNA silencing, effectivelydecreased the concentration of intracellular Ca2+ and pro-liferation of PASMC [53–61]. Song et al. reported thatstromal interaction molecule 2 (STIM2) protein, a Ca2+

sensor in the sarcoplasmic reticulum (SR) membrane, maycontribute to elevated intracellular Ca2+ [62]. What is more,Ca2+ could activate nuclear factor of activated T-cells(NFAT), then suppress K+ channels expression, and lead toPASMC hyperproliferation [63]. It was also proved thathypoxia can cooperate with intracellular Ca2+, which in-creased the expression of aquaporin 1 (AQP1), a membranewater channel, indispensable for PASMC migration. In-creased AQP1 upregulated β-catenin and its target genes(such as c-Myc and cyclin D1), which accelerated theproliferation and migration of PASMC [64–66].

+e normal operation of Na+/H+ exchange (NHE) is es-sential to keep pH homeostasis of PASMC [67, 68]. Studiesshowed that increased expression of NHE isoform 1 (NHE1)can promote the exchange, elevate the pH, and induce theproliferation and migration of PASMC. Although the specificmechanisms are still unclear, it may have something to do withp27 (a cyclin-dependent kinase inhibitor), E2F1 (a nucleartranscription factor), and cytoskeletal re-arrangement [69–75].

4.2. CrucialMolecules. When we talk about PAH, we shouldnever miss hypoxia and hypoxia-inducible factors (HIF).Under the circumstances of hypoxia, increased expressionand decreased degradation result in accumulation of HIF-1α. A lot of studies proved that HIF-1α can influence thePASMC proliferation and mediate pulmonary vascularremodeling, by acting on Ca2+, pH homeostasis, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), andWarburg effect [76–84].

Endothelin is secreted by endothelial cells and has threeisoforms, among which endothelin-1 (ET-1) is the mostwidely expressed and mediates vascular contraction, cellmigration, and proliferation. In terms to PASMC, ET-1binds to ETA or ETB and then has an impact on decreased K+

channels, elevated intracellular Ca2+, and activation ofNHE1 and Rho kinase (ROCK) signaling, leading to themigration and proliferation of PASMC [85–88].

5-Hydroxytryptamine (5-HT) is well known in de-pression mechanism and it also takes part in the develop-ment of PAH. 5-HT enters PASMC through serotonin

transporter (SERT). +e signaling cascades caused by 5-HTinclude increased reactive oxygen species and activation ofmitogen-activated protein kinase (MAPK) and ROCKpathway, which regulate the expression of genes targetingcell growth and influence PASMC [89–93].

4.3. Important Pathways

4.3.1. Rho Kinase. Rho kinase (ROCK) signaling pathwayplays an indispensable part in vascular contraction andremodeling. Exposed to hypoxia, activation of ROCK inPASMC through Rho B (upstream activators of ROCK)could augment the proliferation and migration of PASMC,resulting in increased pulmonary vascular resistance. +erewere studies stating that long-term use of ROCK inhibitorscould ameliorate vascular remodeling [94–103]. Abe et al.reported that PDGF activated ROCK, suppressed thetranslocation of Smad1 originally induced by bone mor-phogenetic protein 2 (BMP 2), and increased PASMCproliferation [104].

4.3.2. BMP Signaling. Bone morphogenetic protein receptortype 2 (BMPR2) mutations are present in patients withheritable and idiopathic PAH, which reminds us of BMPsignaling’s significant role in the development of PAH. +emutation of BMPR2 could inhibit the antiproliferation effectof BMP2, leading to PAH. BMP can exert its function in away of Smad dependent or independent. BMP/BMPR1interacts with Smad1/5/8, then increasing their binding withSmad4, finally leading to elevated related genes expression.In other ways, BMP activates MAPK, PI3K/AKT, or proteinkinase C (PKC) to influence PASMC. +e impaired controlof BMP signaling may be a common characteristic of PH nomatter what the pathogenesis is [105–110] (Figure 1).

4.3.3. Cancer �eories. As mentioned above, at the molec-ular level, PASMC of PAH exhibits many features similar tocancer cells, making it possible to explore potential thera-peutic treatments used in cancer to cure PAH (reviewed in[40]). Studies showed increase of IL-6, monocyte chemo-tactic protein 1 (MCP-1), and tumor necrosis factor alpha(TNF-α) related to worse clinical outcomes in PAH patients.IL-6 knockout effectively ameliorated PAH in animalmodels. Platelet-derived growth factor (PDGF) mediatedmitogenic signaling and thickening of the pulmonary vascularmedia. +ese growth factors and inflammatory mediatorseventually have an impact on cell growth and survival byMEK/ERK, PI3K/AKT, or JAK/STAT3 pathways. In PASMC,it was reported that activation of STAT3 can upregulate theexpression of proviral integration site for Moloney murineleukemia virus-1 (PIM-1) and then enhance NFAT-mediatedtransactivation, resulting in decreased K+ channels and in-creased intracellular Ca2+. In addition, activation of PI3K/AKT and JAK/STAT3 inhibited the transcription factorForkhead box protein O1 (FOXO1), causing elevated CyclinB1 and D1 and decreased p27, which promoted PASMCproliferation [48, 111–122].

International Journal of Hypertension 3

Mammalian target of rapamycin (mTOR) signaling playsimportant roles in cell metabolism, cell proliferation, andsurvival. Together with other proteins, mTOR forms twoindependent complexes, mTORC1 (mTOR-Raptor) andmTORC2 (mTOR-Rictor). Activation of mTORC1 couldenhance ribosomal protein S6 kinase beta-1 (S6K1) andsuppress eukaryotic translation initiation factor 4E-bindingprotein 1 (4E-BP1), which facilitates cell growth and pro-liferation. On the other hand, mTORC2 is more likely torespond to growth factors, increasing cell survival [123–125].However, Tang et al. reported that mTORC1 and mTORC2had different roles in the development of PAH. Inhibition ofmTORC1 ameliorated pulmonary hypertension, while in-hibition of mTORC2 facilitated spontaneous pulmonaryhypertension and it may result from upregulation of PDGFreceptors in PASMC [126].

+e Hippo signaling pathway is believed to relate tocontrolling organ size. It is constitutive of a cascade of tumorsuppressive kinases mammalian STE20-like protein kinase1/2 (MST1/2) and large tumor suppressor homolog 1/2(LATS1/2), while its downstream molecules include yes-associated protein 1 (YAP) and transcriptional coactivatorwith PDZ-binding motif (TAZ). Inactivation of LATS1/2leads to decrease of YAP and TAZ in cytoplasm and acti-vation of HIF-1α and Notch3 pathways, which plays adeleterious role in the development of PAH [127–133].

Most cancer cells rely on aerobic glycolysis, instead ofdepending on mitochondrial oxidative phosphorylation togenerate energy, a phenomenon termed “the Warburg ef-fect.” +is effect also can be seen in PASMC and PAH.Driven by HIF activation, augmented glycolysis is charac-terized by elevated expression of pivotal proteins in itspathway, such as glucose transporters, hexokinase, pyruvatedehydrogenase kinase (PDK), lactate dehydrogenase (LDH),and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase3 (PFKFB3). By interacting with PI3K/AKT, ERK1/2, andHIF-1α and altering the morphology and subcellular dis-tribution of mitochondria, Warburg effect increases theproliferation of PASMC in PAH [10, 134–144].

4.3.4. Other Pathways. Peroxisome proliferator-activatedreceptor c (PPARc) regulates mitochondrial gene expressionand biogenesis. Loss of PPARc leads to derangement inmitochondrial structure and function, which has a harmfulimpact on PASMC and PAH [145]. Xie et al. stated thatleptin effectively ameliorated pulmonary vascular remod-eling and PAH, via activation of ERK1/2 and elevated ex-pression of early growth response-1 (Egr-1), resulting in lossof PPARc [146]. In addition, Li et al. reported that activatingprostanoid EP4 receptor (EP4) also decreased the expressionof PPARc through protein kinase A (PKA) pathway andattenuated pulmonary arterial remodeling [147] (Figure 2).

Cyclin-dependent kinases (CDK) are crucial regulatorsof cell cycle and proliferation. Dinaciclib and palbociclibinhibited specific CDK and decreased PASMC proliferationvia cell cycle arrest and interacted with the downstreamCDK-Rb (retinoblastoma protein)-E2F signaling pathway,offering a potential strategy in PAH [148]. Sphingosinekinase 1 (SphK1) is a lipid kinase for phosphorylatingsphingosine to generate sphingosine-1-phosphate (S1P).SphK1/S1P have been reported to relate to cell proliferation,migration, and survival. TGF-β1 could phosphorylateSmad2/3 and then elevate the expression of SphK1 and S1P,which activates Notch3 pathway to promote PASMC pro-liferation [149]. What is more, Sysol et al. reported thatdecreased micro-RNA-1 induced by hypoxia had an effecton the development of PAH via regulation of sphingosinekinase 1 [150].

5. Potential Treatment to PAH

While calcium channel blockers, endothelin receptor an-tagonists, phosphodiesterase type 5 inhibitors and guanylatecyclase stimulators, prostacyclin analogues, and prostacyclinreceptor agonists are the classical specific drug therapies forPAH, their effects still are limited and unsatisfactory. Basedon the molecular pathways mentioned above, tyrosine ki-nase inhibitors (platelet-derived growth factor inhibitors)and serotonin antagonists are being explored, but present

ET-1 Hypoxia 5-HT BMP

ion channels ET A/ET B SERT BMPR

K+ ↓/Ca2+ ↑/NHE(PH↑) HIF↑ ROCK Smad/PI3K/AKT/PKC

Hyperproliferation and resistance to apoptosis of PASMC

Stimulators

Figure 1: Molecular pathways in PASMC (1). ET-1: endothelin-1, 5-HT: serotonin, BMP: bone morphogenetic proteins, ET A/ET Bendothelin receptor A/B, SERT: serotonin transporter, BMPR: bone morphogenetic proteins receptor, NHE: Na+/H+ exchanger, HIF:hypoxia-induced factor, ROCK: Rho kinase, PI3K/AKT: phosphatidylinositide 3-kinase/protein kinase B, PKC: protein kinase C.

4 International Journal of Hypertension

outcomes are not ideal. Moreover, ROCK inhibitors, VEGFreceptor inhibitors, stem cell therapy, mTOR inhibitors,PPAR-c agonist, and strategies aiming at Warburg effect areall in the early phase of research [15, 142–144, 151, 152].

6. Summary

Although the treatment for pulmonary hypertension hasachieved great improvement, it is still not that satisfactory.Owing to its indispensable role in the development ofpulmonary hypertension, PASMC becomes the research hotspot in PH. Further elucidating the molecular basis ofPASMC, including ion channels, HIF, ET-1, ROCK, BMP,PPAR-c, and Warburg effect, could bring hope to PHtreatment.

Conflicts of Interest

+e authors declare that there are no conflicts of interest.

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PDGF

PPAR-γ

PI3K/AKT JAK/STAT3MEK/ERK

MST1/2

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